Melatonin inhibits microglial activation, reduces pro‐inflammatory cytokine levels, and rescues hippocampal neurons of adult rats with acute Klebsiella pneumoniae meningitis

Abstract

Acute bacterial meningitis caused by Klebsiella pneumoniae (K.pneumoniae) is a major health threat with a high mortality rate and severe neuro-cognitive sequelae. The intense pro-inflammatory cytokine released from calcium-mediated microglial activation plays an important role in eliciting neuronal damage in the hippocampal region. Considering melatonin possesses anti-inflammatory and immuno-modulatory properties, the present study determined whether melatonin can effectively decrease inflammatory responses and prevent hippocampal damage in animals subjected to K.pneumoniae. Adult rats inoculated with K.pneumoniae received a melatonin injection immediately thereafter at doses of 5, 25, 50, or 100 mg/kg. Following 24 h of survival, all experimental animals were processed for time-of-flight secondary ion mass spectrometry (for detecting glial calcium intensity), isolectin-B4 histochemistry (reliable marker for microglial activation), pro-inflammatory cytokine measurement as well as cytochrome oxidase and in situ dUTP end-labeling (representing neuronal bio-energetic status and apoptotic changes, respectively). Results indicate that in K.pneumoniae-infected rats, numerous calcium-enriched microglia, enhanced pro-inflammatory cytokine, and various apoptotic neurons with low bio-energetic activity were detected in hippocampus. Following melatonin administration, however, all parameters including glial calcium intensity, microglial activation, pro-inflammatory cytokine levels, and number of apoptotic neurons were successfully decreased with maximal change observed at a melatonin dose of 100 mg/kg. Enzymatic data corresponded well with above findings in which all surviving neurons displayed high bio-energetic activity. As effectively reducing glia-mediated inflammatory response is neuro-protective to hippocampal neurons, the present study supports the clinical use of melatonin as a potential therapeutic agent to counteract K.pneumoniae meningitis-induced neuro-cognitive damage.